FURTIIER CONTRIBUTIONS TO THE VASCULAR PHYSIOLOGY OF ATOPIC DERMATITIS * ROBERT G. WEBER, M.D., GRACE M. ROTH, PH.D AND ROBERT R. KIERLAND, M.D.

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1 FURTIIER CONTRIBUTIONS TO THE VASCULAR PHYSIOLOGY OF ATOPIC DERMATITIS * ROBERT G. WEBER, M.D., GRACE M. ROTH, PH.D AND ROBERT R. KIERLAND, M.D. Many physiologic aberrations of the autonomic nervous system have been shown by recent investigators (1 4) to exist in patients with atopic dermatitis. We agree that the autonomic nervous system is involved in atopic dermatitis, but conjecture whether this is of a primary or secondary type; that is, are the alterations in this system directly related to the pathogenesis, or is the system secondarily involved? This present work was performed with four goals in mind: 1) to corroborate the previous findings of Eyster, Roth and Kierland (1) in which greater peripheral vasoconstriction in the extremities was demonstrated in patients with atopic dermatitis than in normal subjects when they were exposed to a "cold" room (20 C.), the vasoconstriction persisting to a degree when they were moved to a "hot" room (32 C.), 2) to ascertain whether "cold" was the essential factor in the manifestation of these vasoconstrictive phenomena, 3) to discover if this proclivity to vasoconstriction of the peripheral blood vessels was singularly peculiar to patients with atopic dermatitis and 4) to determine whether the effect of alcohol might illustrate other abnormalities of the peripheral vascular system in this disease. PROCEDURE Selection of Subjects Three categories of subjects were employed, namely 1) patients with atopic dermatitis both acute and subacute, 2) persons without atopic dermatitis but having other manifestations of atopy (for example, asthma, hay fever or urticaria) and 3) normal persons without atopy in themselves or their families (hereinafter designated "controls"). The patients with atopic dermatitis had been hospitalized for the severity of their illness but were otherwise unselected. The other two categories were comprised of physicians, nurses and college students who were engaged in normal activities. Cold-pressor Test This test was performed on all subjects immediately following the skintemperature studies done according to the method outlined by Hines (5). The subjects lay supine. With the cuff of the sphygmomanometer on one arm, the hand of the opposite side was immersed in ice water (4 C.) for 1 minute. Blood- * From the Sections of Dermatology & Syphilology and Physiology, Mayo Clinic and Mayo Foundation, Rochester, Minn. The Mayo Foundation is a part of the Graduate School of the University of Minnesota. Read at the meeting of the Society for Investigative Dermatology, San Francisco, California, June 19,

2 20 THE JOURNAL OF INVESTIGATIVE DERMATOLOGY pressure readings were taken at the end of 30 and 60 seconds. The hand was removed from the ice water as soon as the 60-second reading had been made. The higher of the two readings was taken as an index of response. Skin Temperature Medications were withheld for 20 hours and the subjects were fasted 15 hours before the tests. The subjects wore lightweight, short pajamas and were in a supine position on comfortable beds. Data were obtained in three rooms held at a constant temperature of 25.5 C. (77.9 F.), 21 C. (69.8 F.), and 33 C. (91.4 F.) respectively. In all three rooms the relative humidity was maintained at 40 per cent. The temperature of the plantar surface of the first and third toes of both feet, the palmar surface of the distal phalanges of the first and third fingers of both hands and the skin of the antecubital and popliteal fossae was measured by means of copper-constantan thermocouples at 10-minute intervals. Basal Metabolic Rate Because it has been shown (6 8) that there is an approximately linear relationship existing between the average skin temperature of the toes and the basal metabolic rate obtained under a constant environmental temperature of 25 C. (77 F.) and a relative humidity of 40 per cent, the basal metabolic rate was determined during the control period on the day the skin-temperature studies were made. The basal metabolic rate was determined by a modification of the Tissot gasometric method and the expired air was analyzed in a Haldane gas analyzer. In order to compare the vasomotor tonus of patients who had atopic dermatitis with that of control subjects and that of subjects with other atopy but no dermatitis, skin temperatures were measured by moving the subjects from a comfortable (normal room) 25.5 C. (77.9 F.) to a cooler environment (cold room) of 21 C. (69.8 F.), and later to a warmer environment (hot room) of 33 C. (91.4 F.). When the effect of the warmer environment only was to be adjudged, the subject was transferred directly from the 25.5 C. room to the 33 C. room. The alcohol study was done only in the 25.5 C. environment. Alcohol Studies Ninety-five per cent ethyl alcohol, on the basis of 30 cc. per 150 pounds (68 kg.) of body weight, was diluted with orange juice to a volume of 250 cc. and warmed to 25 C. This was drunk by the subjects after their skin temperatures had become stabilized which usually required a minimum of 60 minutes. These subjects remained in the normal room throughout the entire period of observation. Study Groups The subjects were divided into four study groups to correspond with the four objectives cited previously. Study group 1 consisted of 11 patients with atopic dermatitis (6 males and 5

3 VASCULAR PHYSIOLOGY OF ATOPIC DERMATITIS 21 females) whose ages ranged from 15 to 44 years, and 10 controls (9 males and 1 female) whose ages ranged from 17 to 43 years. These were exposed to the normal, cold and hot rooms consecutively on the same day. (Note: In this paper we shall occasionally use the letters N, H and C to designate "normal," "hot," and "cold" rooms respectively.) Study group 2 consisted of 19 patients with atopic dermatitis (9 males and 10 females) whose ages ranged from 15 to 44, and 14 controls (7 males and 7 females) whose ages ranged from 17 to 43 years. These subjects were exposed to either the N-C-H room sequence or just the N-H room sequence to adjudge any discrepancy arising from exposure to the cold room. Study group 3 consisted of 9 subjects having bronchial asthma, hay fever or urticaria but no dermatitis; there were 1 male and 8 females and the age range was 19 to 31 years. These subjects were exposed to the N-C-H and the N-H room sequence and compared with study group 1. Study group 4 consisted of 10 patients with atopic dermatitis and 10 controls. The usual test which consisted of the oral administration of 30 cc. of 95 per cent alcohol in 250 cc. of orange juice to each person, regardless of size, was altered to correspond to 30 cc. per 150 pounds (68 kg.) of body weight. RESULTS Cold-pressor Test The results of cold-pressor tests are given in the table. The average basal blood pressure and the rise in response to cold in patients with atopic dermatitis were not significantly different from those of the controls. The average rise in blood pressure, expressed in millimeters of mercury, was slightly less than that obtained by Eystcr, Roth and Kierland (1) but the "ceiling" pressure attained was the same. In the category of patients with atopic dermatitis the response of the diastolic blood pressure to cold was higher than the normal response of Hines (5) (namely, 20 mm. in systolic and 15 mm. in diastolic pressure). In 9 patients the rise of systolic pressure was greater than 20 mm. and in 18 patients the rise of diastolic pressure was greater than 15 mm. There was no selection of the 18 control subjects, of whom 9 had a rise of systolic blood pressure that was greater than 20 mm. of mercury and a diastolic TABLE Results of the cold-pressor test Average blood pressure, mm. of Hg Category Cases Cold-pressor tests Basal Di- Systolic astolic Cold-pressor. Di- Systohc astolic Systolic Rise Atopic dermatitis... Atopy without dermatitis Controls

4 22 TIlE JOURNAL OF INVESTIGATIVE DERMATOLOGY rise that was greater than 15 mm. In a previous study of a normal group by Roth and Sheard (8), no significant difference in response to the cold-pressor test occurred after exposure to a warm environment and the oral administration of alcohol. In the 9 subjects with atopy without dermatitis there was a normal response of the blood pressure. Skin Temperature Study group 1. The correlation of vasomotor changes as demonstrated by measurement of skin temperature of the extremities and by the basal metabolic rate is illustrated in figure 1, which depicts the variations in time and degree of cooling and warming related purely to a differential in the basal metabolic rates of control subjects moved from a temperature of 25.5 C. to a cooler one of 21 C. and subsequently to a warmer temperature of 33 C. This must be borne in mind throughout the entire study in order that the results may be evaluated properly. In figure 2 one may see graphically the averages of 10 controls and 11 patients with atopic dermatitis exposed to the N-C-H room sequence. In assaying figure 2 one finds that the greatest fluctuation of temperature occurs in the skin of the toes, and then the fingers, the antecubital and popliteal fossae respectively. Normal Normal 50 mm. 70 iin nm. 40 mm. 60 mm. 70 mm. Fxo. 1. Variations in time and degree of cooling and warming related purely to a differential in the basal metabolic rates of control subjects moved from a temperature of 25.5 C. to a cooler one of 21 C. and subsequently to a warmer one of 330C. (From Eyster, W. H., Jr., Roth, Grace M. and Kierland, R. R.: Studies on the Peripheral Vascular Physiology of Patients With Atopie Dermatitis. J. Invest. Dermat. 18: [Jan.] 1952.)

5 VASCULAR PHYSIOLOGY OF ATOPIC DERMATITIS 23 Normal dr'ou Atopic dermatitis Time in minutes *CCL1. per' sq meter per hr' FIG. 2. Variations in the temperature data on 10 controls and 11 patients with atopie dermatitis exposed to the N-C-H room sequence. (For the purpose of clarity in our figures, we did not graph the skin temperatures of the popliteal fossa since they would be either superimposed or closely allied to those of the antecubital fossa.) The fingers and toes of the patients with atopic dermatitis have initially lower temperatures, cool to a greater degree per unit time and warm more slowly and to a lesser degree ultimately than in control subjects. In contrast, in 8 of the 11 patients with atopic dermatitis the skin temperatures of the antecubital and popliteal fossae during exposure of the patients to the N-C-H room sequence were higher than in control subjects. In 6 of 11 patients with atopic dermatitis the toes never attained a skin temperature equivalent to the hot-room temperature. In these 6 patients the disease was in the acute stage as manifested by erythema and exudation in the involved areas, and wet dressings had recently been applied. In the 5 remaining patients the disease was in a "subacute" phase, in which erythema and exudation were minimal or lacking and treatment consisted of the use of tar and ultraviolet light. It is noteworthy that 2 of 10 controls, when moved to the warm room, manifested a feature identical to one in patients with "acute" atopic dermatitis, namely inability of the toes to reach room temperature. However, these 2

6 24 TRE JOURNAL OF INVESTIGATIVE DERMATOLOGY Time in minutes *CO.1. per' s. meter per hr Fio. 3. Variations in the temperature data on patients with atopic dermatitis, 11 of whom were exposed to the N-C-H room sequence and 13 of whom were moved directly from the normal to the hot room. controls exhibited grade 3 sweating on the extremities (graded on a basis of 1 to 4) while the atopic patients did not. This is cited to emphasize the need to determine sweating. Study group 2. In figure 3, again measurements of skin temperature of a group of 11 patients with atopic dermatitis who were exposed to the N-C-H room sequence are compared with alterations of skin temperature of a group of 13 patients with atopic dermatitis who were moved directly from the normal room to the hot room, circumventing the cold room completely. It is readily apparent that a similar response of delayed warming occurred without antecedent exposure to the cold room. The ultimate temperatures attained in the warm room are likewise similar though stabilization occurred at a slightly higher temperature but with a corresponding increment in time in the group which was not exposed to the cold room. This was true of all sites tested. Of the subjects on which figure 3 is based, 5 were used in both series to rule out individual variation. Comparison of these paired results disclosed that they were analogous to the results shown for the 19 patients.

7 VASCULAR PHYSIOLOGY OF ATOPIC DERMATITIS Time in minutes *CQ1. per sq. meter per hr FIG. 4. Variations in the temperature data on controls exposed to the N-C-H and to the N-H room sequence respectively. Determinations were made on an analogous series of 14 controls to establish whether any differential in warming was produced by exposure of the controls to the cold room (fig. 4). On exposure to the cold room there was delay in warming to comparable end points as noted, the cold room engendering a universal but mild delay in warming of sites tested. Of the controls on which figure 4 is based, 5 were used in both series to rule out individual variation. Comparison of these paired results disclosed that they were similar to those shown for the control subjects. Study group 3. In this group, consisting of 9 subjects with asthma, hay fever or urticaria (but not dermatitis), none were tested during activity of their disease. Figure 5 portrays the changes in skin temperature of these atopic subjects on exposure to both the N-C-H room sequence and the N-H room sequence. The results are similar to those obtained in the patients with atopic dermatitis in respect to the fluctuations of temperature in the toes, fingers and flexural surfaces (that is, the toes and fingers underwent a greater degree of cooling per

8 26 TEE JOURNAL OF INVESTIGATIVE DERMATOLOGY Group with cttopy (exclusive of dermatitis) Time in minu.tes * Cci. per sq. meter per he Fio. 5. Variatious in the temperature data on atopic subjects without dermatitis on exposure to the N-C-H and to the N-H room sequence respectively. unit of time and a slower rate of warming, and the antecubital and popliteal fossae showed a lesser degree of coolin8 and a greater degree of warming per unit of time than in the controls). The basal metabolic rates in atopic subjects without dermatitis (32.8 and 33.3 calories per square meter per hour) are slightly lower than those for the controls (36.7 and 34.6 calories per square meter per hour), whereas the basal metabolic rates of the patients with atopic dermatitis are similar to those of the controls. We do not believe the basal metabolic rates are of great enough variance to be responsible for the observed differences. Study group 4. In figure 6 it is seen that the patients with atopic dermatitis again demonstrated a lower basal temperature of the toes and fingers and a higher basal temperature of the antecubital fossa than did the controls. When compared with the controls the patients with atopic dermatitis manifested a greater increase in the temperature of the toes, a similar increase in the fingers, and a lesser increase in the antecubital fossa (though the ultimate temperature of the latter site is higher in the patients with atopic dermatitis than in the controls, and the reverse is true of the fingers). The fact that the incipiency of

9 VASCULAR PHYSIOLOGY OP ATOPIC DERMATITIS Time in minu.tes *CcLl. per' sq. meter per' lir FIG. 6. Variations in temperature data on controls and on patients with atopic dermatitis in the group in which alcohol was given. the rise at each site tested was similar for the categories in this group suggests that the absorption variable of the alcohol was similar in both. On scrutiny of the individual skin temperatures in both categories of group 4, however, it was noted that both have representatives that are markedly erratic in response, with no universal trend. Five of the 10 controls and 3 of the 10 patients with atopic dermatitis showed a rise in temperature of only 2 C. or less in both the toes and the fingers. COMMENT The patients with atopic dermatitis manifested a greater degree of cooling per unit time and a slower rate of warming of the toes and fingers than control subjects, corroborating the previous work of Eyster, Roth and Kierland (1) reporting vasoconstriction of these sites. Another feature indicating vasoconstriction was an initially lower basal temperature of the fingers and toes compared with control subjects having comparable basal metabolic rates. However, temperatures of the antecubital and popliteal fossae in patients with

10 28 THE JOURNAL OF INVESTIGATIVE DERMATOLOGY atopic dermatitis did not react in a similar fashion but in contrast demonstrated a lesser degree of cooling per unit time and a faster rate of warming. The subjects with atopy other than dermatitis demonstrated temperatures that were identical in the antecubital and popliteal fossae and similar in the toes and fingers to those of the patients with atopic dermatitis. We had thought that in the patients with atopic dermatitis the tested flexural areas (that is, the antecubital and popliteal fossae) responded in the indicated manner because of the active inflammatory process which obviously prevailed. However, when we noted that patients with "acute" atopic dermatitis had temperatures identical to those in the "subacute" stage and that those with atopy other than dermatitis manifested the same features, an acute inflammatory process alone became untenable as a basis for explaining this proclivity of the tested flexural sites to exhibit a lesser degree of cooling per unit time and a faster rate of warming. It seems as if the physical stress of change of environmental temperatures (that is, heat and cold) produces two distinct phenomena in patients with atopy, namely (1) a tendency to decreased vasoconstriction in the antecubital and popliteal fossae and to increased vasoconstriction in the toes and fingers in the cold room and (2) delayed vasodilation of the toes and fingers and somewhat increased vasodilation of the antecubital and popliteal fossae in the hot room, as compared with control subjects. This apparently indicates that the autonomic nervous system of subjects with atopy (including dermatitis) is fundamentally different from that of control subjects. It was seen that exposure to the cold room was not a prerequisite for the abnormal temperatures recorded in the hot room in persons with atopy, since the same results are recorded on circumventing the cold room. Thus, it appears that relatively small temperature differentials are as effective as those of greater magnitude in eliciting abnormal peripheral vascular responses in persons with atopy. Patients with acute atopic dermatitis manifested more vasoconstriction of the toes and fingers (the degree of flexural reaction was similar) than those in the subacute phase. This might be explained by the more widespread inflammatory process existing in the former with a compensatory vasoconstriction of the acral areas. In the hot room, because of excessive sweating, the skin temperature of the fingers and toes of 2 control subjects showed vasoconstriction of the peripheral blood vessels similar to that of the patients with atopic dermatitis. The patients with atopic dermatitis occasionally manifested grade 1 sweating in the hot room but never the grade 3 or 4 sweating seen in these 2 controls. This indicates the necessity of noting the degree of sweating to evaluate results, and reflects the lower acral temperatures obtained when heat dissipation is high in other areas. Also, the lesser incidence of profuse sweating in patients with acute atopic dermatitis could be explained by the marked dissipation of heat by the vasodilatation accompanying inflammation, and thus, the lack of need for associated heat dissipation through sweating.

11 VASCULAR PHYSIOLOGY OF ATOPIC DERMATITIS 29 The results of the alcohol study did not demonstrate abnormal vascular physiology in patients with atopic dermatitis. The cold-pressor tests indicated a corroboration of the vascular hyperreactivity of patients with atopic dermatitis as shown by Eyster, Roth and Kierland (1) (under the conditions employed). Persons with other atopy demonstrated a normal response. However, our controls also indicated a hyperreactor group. One explanation of the paradox is the possible derangement that might result from the fact that the cold-pressor testing was done subsequent to hotroom exposure, since there would be an initially greater peripheral vasodilatation at this time and the cold stimulus would be relatively greater. SUMMARY The previous observations of Eyster, Roth and Kierland that peripheral vasoconstriction of the fingers and toes occurs in patients with atopic dermatitis on exposure to a cold room and then to a hot room were corroborated. Concomitant observations of the temperatures of the antecubital and popliteal fossae, however, demonstrated less vasoconstriction in the cold environment and more rapid vasodilation in the warm environment. Exposure to the cold room was not a prerequisite for the abnormal temperatures recorded in the hot room in patients with atopic dermatitis since similar results were recorded when the cold room was circumvented. Thus, it appears that relatively small temperature differentials are as effective as those of greater magnitude in eliciting abnormal peripheral vascular responses in patients with atopic dermatitis. Ninety-five per cent ethyl alcohol given orally demonstrated no abnormal physiology in patients with atopic dermatitis in this sampling and under the conditions cited. Persons with atopy other than dermatitis, namely bronchial asthma, hay fever and urticaria, upon movement from the cold room to the warm room demonstrated temperatures that were identical in the antecubital and popliteal fossae and similar in the toes and fingers to those in patients with atopic dermatitis. This finding correlates with the clinically recognized association of these disease entities. REFERENCES 1. EYSTER, W. H., Ja., ROTH, Gacz M. AND KIERLAND, R. II.: Studies on the peripheral vascular physiology of patients with atopic dermatitis. J. Invest. Dermat., 18: 37 45, GRAHAM, D. T. AND WOLF, STEWART: The relation of eczema to attitude and to vascu lar reactions of the human skin. J. Lab. & Clin. Med., 42: , CoiMiA, F. E.: Basic concepts in the production and management of the psychosomatic dermatoses I. Brit. J. Dermat., 63: 83 92, Kzpzcs, J. G., ROBIN, MILTON AND BRUNNER, M. J.: Relationship between certain emotional states and exudation into the skin. Psychosom. Med., 13: 10 17, HINES, E. A., Ja.: The significance of vascular hyperreaction as measured by the coldpressor test. Am. Heart J., 19: , 1940.

12 30 THE JOURNAL OF INVESTIGATIVE DERMATOLOGY 6. MADDOCE, W. G. AND COLLER, F. A.: The role of extremities in the dissipation of heat. Am. J. Physiol., 106: , SHEARD, CHARLES AND WILLIAMs, M. M. D.: Skin temperatures of the extremities and basal metabolic rates in individuals having normal circulation. Proc. Staff Meet., Mayo Clin., 15: , ROTH, GRACE M. AND SHEARD, CHARLES: Relation of basal metabolic rate to vasodilatation and vasoconstriction of the extremities of normal subjects as measured by skin temperatures. Circulation, 1: , DISCUSSION DR. STEPHEN ROTHMAN, Chicago, Ill.: Drs. Kierland, Eyster, Roth and Weber have made significant contributions to the problem of increased vasoconstrictor tendency of the skin in atopics. It might be worthwhile to point out that this tendency can be demonstrated in a great many ways. If vasoconstrictor stimuli are applied, such as pressure or cold, the vasoconstrictor response is grealy prolonged and intensified. If vasodilator stimuli are applied such as acetylcholine or nicotinic acid esters a paradoxical vasoconstriction ensues in atopic individuals. However, this phenomenon reflects purely an abnormality of the contractile elements of the small blood vessels of the skin and has nothing to do with the innervation of these vessels. The white line on stroking can be produced with the same intensity in denervated areas as in normally innervated skin. Dr. Bloom carried out some experiments in our clinic pertaining to this point on atopics. He interrupted all nervous pathways by block anesthesia of the brachial plexus on one side and applied pressure and acetylcholine stimulation to both sides simultaneously. There was no difference between responses on the normal and blockaded side. Although it is most gratifying to have found a clear-cut pathophysiological feature in the skin of atopics we should not jump to the conclusion that this feature proves the nervous origin or nervous relations of this disease. The phenomenon has nothing to do with nerves. DR. THEODORE CORNBLEET, Chicago, Ill.: I think the phenomenon shown here in people with eczema is not confined to the blood vessels alone. In other ways too it is characteristic for eczema to show sluggish response to certain stimuli such as ability to neutralize alkali. It may stem from a temporary overwhelming by stress. Thus, in the white line response of eczema just spoken of we were able to eliminate it by the administration of cortisone. Hydrocortone locally will partially do away with it. It would be interesting to know what would happen to subjects with eczema tested for vascular responses if they were changed to a cold environment from the warm one and back again. Would they then overshoot the normal levels, and could steroids help them make up the difference?